Drug Class 14: NSAIDs (Selective and Non-Selective) and Paracetamol

Drug class 14: NSAIDS (Non-steroidal anti-inflammatory drugs)

• Non-selective NSAIDs (COX-1 and COX-2 inhibitors)

-Aspirin

-Diclofenac (Can be in combination with misoprostol)

-Ibuprofen, Indomethacin

-Ketoprofen, Keterolac

-Mefenamic acid, Naproxen

-Piroxicam, Sulindac, Tiaprofenic acid

Acronym: I sued Khoo Teck Puat for picking me an ass, dinosaur named ketorolac.

• Selective NSAIDs (COX-2 selective)

– Wrong assumption made: Scientists thought that PGI2 only came from COX-1 however COX-2 also produces PGI2.

-Absence of COX-2 in platelets. Thus, inhibition of COX-2 will lead to depressed PGI2 production, elevated blood pressure, accelerate atherosclerosis (Thromboxane A2 not balanced), Predispose patients to an exaggerated thrombotic effects

-Increased risk of rupture of atherosclerotic plaque.

-Celecoxib

-Etoricoxib

-Meloxicam

-Parecoxib

Acronym: So, they compensated me with a parrot and tori

 

14.1 Mechanism of action:

1. All inhibit the action of cyclo-oxygenase (COX 1 or 2). This enzyme produces prostaglandins from arachidonic acid which is cleaved from the phospholipid membrane by Phospholipase A2.

-Inhibition of COX will prevent production of COX as well as other mediators such as thromboxane.

2. *COX-1 is to produce PGE₂ and PGI₂ which has cyto-protective actions and prevents acid damage to the stomach.

Thus, Inhibition of COX-1 results in impaired gastric cytoprotection and anti-platelet effects.

3. Inhibition of COX-2 results in anti-inflammatory and analgesic action.

4. Reduction in glomerular filtration rate and renal blood flow occurs with both COX-1 and COX-2 inhibition.

Note: Most NSAIDs are non-selective, inhibiting both COX-1 and COX-2. COX-2 inhibitors however, have little or no effect on COX-1 at therapeutic doses but they are still associated with GIT adverse effects.

Major effects of NSAIDS:

-Anti-pyretic

-Anti-inflammatory

-Analgesic

-Anti-platelet (Aspirin, low dose)

-Anti-premature labour

14. 2 Clinical Indications:

(a) Rheumatoid arthritis-Including juvenile idiopathic arthritis

(b) Osteoarthritis

(c) Other inflammatory arthropathies-e.g. ankylosing spondylitis, Psoriatic arthritis, Reiter’s syndrome (Reactive arthritis)

(d) Acute gout

(e) Pain especially due to inflammation and tissue injury (e.g. menstrual pain, metastatic bone pain, renal colic, headache, migraine, post-operative pain)

(f) Fever

14.3 Precautions:

• Allergic reactions to NSAIDs (including aspirin): Contraindicated

• Asthma-Especially with rhinitis or nasal polyps-Contraindicated (May trigger bronchospasm/Aspirin induced asthma)

• Coagulation disorders

-Increased risk of bleeding with NSAIDs (non-selective)àCOX-1 in platelets also inhibited, no thromboxane A2 [Especially at high doses]

-Selective NSAIDs (COX-2 inhibitors) and possibly diclofenac increase risk of thrombosis (Inhibits production of PGI2 in endothelial cells)

• Bruising

-Increased risk of bleeding with topical NSAIDs.

• Cardio/cerebrovascular disorders

-NSAIDs increase risk of cardiovascular events e.g. stroke and MI (Why? Because at high doses, PGI2 production also inhibited thus increased risk of thrombosis)

-Heart failure and hypertension may worsen due to sodium and fluid retention from NSAID-induced reduction in GFR and renal blood flow.

• Gastrointestinal

-Contraindicated in active peptic ulcer disease/GI bleeding

-Avoid all NSAIDs if there is a history of GI bleeding (use with extreme caution and use prophylaxis)

-Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) may worsen.

• Renal impaired

-Pre-existing renal impairment increases the risk of NSAID-induced impairment

-Non-selective NSAIDs increase the risk of bleeding.

*Avoid use if Creatinine clearance CrCl <25ml/min (Celecoxib and Etoricoxib are contraindicated if CrCl<30ml/min)

-Avoid Ketorolac

• Hepatic impaired

-Use with caution in severe impairment (coagulation factors production inhibited). Non-selective NSAIDs increase the risk of bleeding.

-Selective NSAIDs (COX-2 inhibitors) are not recommended.

• Surgery

-Risk of renal impairment after surgery (Especially if dehydrated or renal hypoperfused-Reduced renal blood flow increases the importance of intra-renal prostaglandins in maintaining renal function-Compensatory vasodilation)

-Ensure adequate hydration before surgery, particularly when an NSAID is to be used for post-operative analgesia.

-Increased risk of bleeding with non-selective agents due to anti-platelet effects

-Consider stopping NSAID (2-3 days) before surgery, especially if there is a significant risk of post-operative bleeding.

*Note: Selective NSAIDs (COX-2) do not affect platelet aggregation but may increase risk of thrombotic events.

• Elderly

-Increased risk of adverse effects, in particular heart failure, GIT ulceration and renal impairment.

• Women

-Reconsider NSAID use if planning pregnancy

*May impair fertility by preventing or delaying ovulation (however, this is reversible)

• Pregnancy/Breastfeeding

-Increased risk of miscarriage

-Risk appears highest when NSAIDs are taken around the time of conception

-Contraindicated during the latter part of pregnancy-

–Closes the ductus arteriosus of fetus, leads to fetal renal impairment, decrease in the volume of amniotic fluid, inhibition of platelet aggregation, may delay labor and birth.

-CAT C-AUS

Breastfeeding: Safe to use, selective NSAIDs appear to be safe

14.4 Adverse effects/Side effects

-Common

1. Nausea

2. Gastrointestinal disturbances (dyspepsia, GI ulceration or bleeding)

3. Raised liver enzymes

4. Salt and fluid retention

5. Headache, dizziness

6. Hypertension

*Diarrhea-Mefenamic acid

-Infrequent

Oseophageal ulceration, rectal irritation (with suppositories), heart failure, hyperkalemia, renal impairment, confusion, bronchospasm, rash

Topical use: Skin irritation, erythema, itching and rash

–Rare

MI, Stroke, photosensitivity (JIA-naproxen), acute renal failure, SJS, blurred vision, hypersensitivity, urticarial, nephrotic syndrome, interstitial nephritis, blood dyscrasias

Topical use: Dyspnea, nausea, dyspepsia, abdominal pain, gastritis, contact dermatitis, allergy, peripheral edema

Important information when choosing NSAIDs

• Efficacy: Little difference in anti-inflammatory efficacy between NSAIDs, choice is dependent on individual response and tolerance.
• Route of administration:

-Enteric coated and rectal formulations (do not reduce risk of GI ulceration, i.e. GI risk still present)

-Rectal administration may be useful alternative to oral route (Diclofenac, indomethacin, and ketoprofen are available as suppositories)-Acronym: suppositories for KID

-Topical NSAIDs achieve highest concentration in tissues under application site.

-Small amount absorbed into systemic circulation when topically applied.

-NSAIDs versus Paracetamol?

• Toxicity

Note: Non-selective NSAIDs vary in their half-life and relative toxicity!

Selective COX-2 inhibitors have similar adverse effects to the non-selective agents

-Risk of GI complications and thrombotic events may differ.

• Cardiovascular effects

-All NSAIDs can worsen existing cardiovascular disease (e.g. by increasing BP and reducing renal function)

-Selective NSAIDs (COX-2 Inhibitors) are associated with an increased risk of CV events (especially if low dose aspirin is not taken simultaneously)

*However, when low dose aspirin is taken with COX-2 inhibitor, the risk of GI adverse effects is the same as that with a non-selective NSAID.

-Increased risk of CV events for diclofenac and indomethacin whilst naproxen neither increased nor decreased risk.

• Gastrointestinal effects

*All NSAIDs can cause serious GI adverse effects.

-Selective NSAIDs (COX-2 inhibitors) are generally associated with a lower risk of GI complications than non-selective agents

-Non-selective NSAIDs (especially Ketoprofen and piroxicam) appears to have highest risk of GI-complications. Diclofenac and ibuprofen appear to have the lowest.

-Advantage is lost for ibuprofen when used at full doses.

From the above, it is evident that not all NSAIDs are created equal (e.g. diclofenac and ibuprofen àLess GIT disturbances, diclofenac and indomethacinàLess CV risk)

14.5 Patient Counselling

-If patient develops swollen ankles, difficulty in breathing, black stools or dark-coffee-coloured vomit, stop taking medicine (suggests internal bleeding).

-Tell doctor immediately.

-Do not take aspirin for pain relief as it will increase the risk of side effects with NSAIDs.

14.6 Practice Points

-About 60% of patients will respond to any NSAID. Those who do not respond to one may respond to another.

Qn: Why would patients not respond to a particular NSAID?

Osteoarthritis: Maximal analgesic and anti-inflammatory effects are usually seen within 2 weeks. If appropriate responses are not observed within 3 weeks, try another NSAID.

Note: There is no rationale for using more than 1 NSAID at a time (excluding low dose aspirin for anti-platelet effects)

*For extra pain relief, NSAIDs may be used with paracetamol and if pain is severe use an opioid (e.g. morphine for tumour metastases in bone)

-Seek specialist advice if patient has aspirin induced asthma and great need for an NSAID (may be able to tolerate a selective COX-2 inhibitor, first dose should be given under medical supervision)

*Do not stop low-dose treatment when using an NSAID (NSAID has very weak anti-platelet effects)

*Measure blood count, creatinine and liver function before starting treatment. Repeat at least once a year during continued treatment.

*To reduce complications,

Use the lowest effective dose for the shortest period of time.

Use Paracetamol to enable lower doses of NSAID

-Use of the proton pump inhibitors (omeprazole) or misoprostol (PGE1 analogue) with an NSAID and in patients who are high risk of GI adverse effects

*14.7 Types of NSAIDs (Note NSAIDs are different in side effects, potency for COX-1 and COX-2, route of administrations etc.)

Non-selective NSAIDs

1. 1.       Aspirin (Refer to drug class 12)

• Diclofenac (Voltaren®)

2-(2,6-dichloranilino) phenylacetic acidàDiclofenac

• Clinical indications:

(a) Rheumatoid arthritis*

(b) Osteoarthritis*

(c) Pain, especially due to inflammation (e.g. period pain)

(d) Local pain and inflammation in soft tissues (1% topical gel)

(e) Actinic keratosis- premalignant condition where thick, scaly, or crusty patches of skin are       present in people who are exposed to sun frequently

(f) Heavy menstrual bleeding (dysmenorrhea)

(g) Combination with misoprostolàIndication for Diclofenac and prevention of NSAID induced ulcers

• Precautions

–          Proctitis (inflammation of anus)-Use of suppositories is contra-indicated

–          Increased cardiovascular risk-Avoid diclofenac (may increase risk of CV events)

• Practice points

Combination with misoprostol

-Consider only for patients already stabilised on the same dose of single ingredient products because optimum dose of misoprostol to prevent NSAID-related gastric ulcers (800 mcg daily) prevents use of the lowest effective dose of diclofenac.

-Misoprostol is poorly tolerated due to adverse effects (diarrhea) and may lead to inadequate dosing of NSAID.

• Ibuprofen

(Iso-butyl-propanoic-phenolic acid)

• Clinical indications:

(a)    Rheumatoid arthritis*

(b)   Juvenile (child) idiopathic arthritis (JIA)-Common form of arthritis in children and adolescents

(c)    Pain, especially due to inflammation (e.g. period period, headache)

(d)   Fever

(e)   Heavy menstrual bleeding (dysmenorrhea)

*Combination with codeine-Mild to moderate pain

• Precautions:

-Patients on low-dose aspirin (ibuprofen may reduce aspirin anti-platelet activity)

• Counselling

-Take oral doses with or shortly after food

• Practice points

–Infants and children tolerate low grade fever (e.g. <38-38.5^oC) well, often responds to fluids and comfort. May not need medication.

Recall: Fever is due IL-1 and IL-6 effects on the hypothalamus which causes an increase in set point for body temperature.

Note: Ibuprofen may reduce anti-platelet activity of low dose aspirin and potentially reduce or negate its cardio-protective effect.

*Never take ibuprofen and aspirin together.

-Unlikely, that an occasional dose of ibuprofen would have a clinically important effect.

-Choose an alternative NSAID if regular use is anticipated.

• Indomethacin/Indometacin

(indole ring present, methoxy group present)

• Clinical indications:

(a)    Rheumatoid arthritis*

(b)   Osteoarthritis*

(c)    Acute gout

(d)   Ankylosing spondylitis (Fusion of the vertebrae due to inflammation)

(e)   Pain, especially due to inflammation (e.g. period pain)

(f)     Closure of significant patent ductus arteriosus (seek specialist advice)

Precautions:

Proctitis-use of suppositories is contraindicated.

Adverse effects:

*Vertigo (Common)

Counselling points:

-Take capsules with or shortly after food

-This medication may affect patient alertness and coordination. Avoid tasks such as driving or operating equipment.

• Ketoprofen

(RS)2-(3-benzoyl linked via ketone to phenyl)-propionic acid

• Clinical indications:

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Superficial sport injuries and similar injuries (topical)

• Precautions:

-Procitis (Use of suppositories contraindicated)

• Practice points:

-Capsules or suppositories may be used at bedtime to relieve nocturnal and morning symptoms

• Ketorolac

(Dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin)

(Isostere of ketoprofen)

• Clinical Indications:

*Mild-to moderate post-operative pain

• Precautions:

1.  Cautions where risk of bleeding is increased or hemostasis is critical (e.g. full anti-coagulation treatment, increased risk of haemorrhage, suspected intracranial bleeding, history of GI ulcer etc)

2. Dehydration or hypovolemia-Contraindicated

3. Treatment with probenacid-Contraindicated

4. Treatment with aspirin-Contraindicated

5. Treatment with lithium-Contraindicated

6. Treatment with oxpentifylline (treats peripheral vascular disease)-Contraindicated

*Note: DO NOT GIVE KETOROLAC WITH ASPIRIN OR PROBENACID.

 

7. Renal impaired-Contraindicated

-Contraindicated in moderate-to-severe impairment (renal impaired increases the half-life of ketorolac)

-Increases risk of adverse effects such as acute renal failure (Reduce dose in mild impairment)

8. Elderly

-Half-life of ketorolac may be prolonged, increasing risk of adverse effects. Reduce dose for elderly.

• Adverse effects/Side effects

Common

1. Pain at injection site
2. Swelling
3. Purpura

Infrequent

-Perioperative wound bleeding

Rare

-Brusing, hematoma or tingling at injection site

• Administration advice/Practice points

IM INJECTION: Inject slowly and deeply into muscle. Apply pressure at injection site for 15-30 seconds (minimises local reactions)

IV: Inject over at least 30s

-Correct hypovolemia before administering ketorolac

-Higher than recommended doses increase risk of serious adverse effects without improving pain relief

-Risk of adverse effects may increase with prolonged treatment. Stop treatment ASAP.

 

• Mefenamic acid (‘Me fend a mic’)

• Clinical Indications:

(a)    Pain especially due to inflammation (e.g. period pain)

(b)   Heavy menstrual bleeding (dysmenorrhea)

• Side effects/Adverse effects:

Common

-Diarrhea

• Naproxen (naproxen sodium)

(+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid

• Clinical indications:

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Ankylosing spondylitis

(d)   Juvenile idiopathic arthritis (JIA)

(e)   Pain, especially due to inflammation (e.g. period pain, dysmenorrhea, migraine)

(f)     Heavy menstrual bleeding (Accepted)

• Adverse effects/Side effects:

Pseudoporphyria (particulary in JIA) Common-Photosensitivity

• Counselling:

*Take with or shortly after food

-JIA (juvenile idiopathic arthritis): Risk of skin reaction with naproxen (often with blisters and scars). Tell doctor if this occurs.

• Practice Points:

-Naproxen can reduce the anti-platelet activity of low-dose aspirin

-Potentially negate or reduce aspirin’s cardio-protective effect

*Stop naproxen if pseudoporphyria occurs

-Controlled release products can be taken at night to relieve nocturnal and morning symptoms

-Oral liquid contains 8mg/ml of sodium

• Piroxicam (Pirate oxi cam)

Contains pyridine ringàPiroxicam

• Clinical indications: (a) Rheumatoid arthritis (b) Osteoarthritis (c) Ankylosing spondylitis (d) Superficial sports injuries and similar injuries

• Precautions:

-Previous skin reaction with piroxicam-[Use of oral piroxicam is contraindicated, even if reaction was mild]

-Previous severe allergic reaction to any drug-[Use of oral piroxicam is contraindicated]

• Counselling:

-Take tablets or capsules with or after food

-If patient develops a rash, stop taking piroxicam and tell the doctor.

• Practice points:

-Serious skin reactions may be more frequent with piroxicam than with other NSAIDs.

• Sulindac (arylalkanoic acid class)-Prodrug

{(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-indene-3-yl}acetic acidàSulindac

• Clinical indications: (a) Rheumatoid arthritis (b) Osteoarthritis

 

• Adverse effects:

-Renal stones (Rare)

 

• Tiaprofenic acid (The ‘profanitic ‘acid) (Class: arylpropionic acid (profen) class)

(Contains Thienyl and propanoic acid)

• Clinical indications

 

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

• Precautions

-Urinary tract or prostatic disease (may worsen)

-Renal impaired: Reduces excretion

-Contraindicated in cystitis and Urinary Tract Infection

• Adverse effects

–Cystitis, bladder irritation (Rare)

• Pharmacokinetics

Metabolism: Sparingly metabolised in the liver to two inactive metabolites.

-Excretion: Mostly excreted unchanged in the urine (Caution in Renal impaired)

 

• Selective COX-2 inhibitors (Caution needed when used in patients with cardiovascular problems)

-Risk of allergies due to sulphonamide group present and contraindicated in hepatic impaired.

– Ratio of Drug selectivity for COX-1 to COX-2= (IC 50 FOR COX-1)/(IC 50 FOR COX-2)

-Smaller ratio, more selective to COX-2

 

 

• Celecoxib (COX-2 selective)

 

• Clinical Indications

 

 

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Ankylosing Spondylitis

(d)   Pain due to dysmenorrhea or injury (soft tissue injury, musculoskeletal, post-operative)

• Precautions

 

1. Allergy to sulphonamides (may increase risk to celecoxib) [Contraindicated]
2. Cardiovascular (Contraindicated in Heart failure)
3. Contraindicated for pain due to Coronary Artery Bypass graft (CABG)
4. Hepatic impaired. Contraindicated in severe hepatic impairment. Mild to moderate impairment reduces clearance and increases concentration. Reduce dose.

 

• Practice points

-Same no. of gastric ulcerations in celecoxib and non-selective NSAIDs (so what is the advantage of COX-2 inhibitors?)

• Etoricoxib (COX-2 selective) [E-tori coxib]

 

• Clinical indications:

(a) Osteoarthritis

(b) Acute gout

(c) Acute pain (e.g. period pain)

• Precautions:

Contraindicated in:

 

1. Cardiovascular (contraindicated by manufacturer in patients with heart failure. NYHA II-IV)
2. BP>140/90 mmHg (inadequately controlled hypertension)-Etoricoxib more likely to induce hypertension
3. Coronary heart disease, cerebrovascular disease or peripheral arterial disease

Use cautiously in others at increased cardiovascular risk: May increase risk of thromboembolic events

*Hepatic impaired-Contraindicated in severe impaired.

 

• Practice points:

–Measure BP within 2 weeks, then repeat periodically, stop etoricoxib if BP rises significantly.

• Meloxicam (Mel oxi cam)

 

• Clinical Indications:

 

(a)    Osteoarthritis

(b)   Rheumatoid arthritis

• Practice Points:

-Use the lowest effective dose, as the COX-2 selectivity of meloxicam is dose-dependent

-15mg dose provides greater pain relief than 7.5 mg dose but higher risk of GI adverse effects.

*Not indicated for relief of pain unrelated to arthritis (contraindicated for pain management in CABG)

-Although drug interactions involving CYP enzymes do not appear to be problematic, combination with CYP2C9 inhibitors is contraindicated in AUS product information.

• Parecoxib (‘Parent coxib’)-Prodrug

–

-Water soluble and injectable prodrug of valdecoxib.

• Clinical Indications:

*Post-operative pain (single dose)

• Precautions:

1. Increased risk of cardiovascular events (.e.g those with ischemic heart disease, peripheral arterial disease or cerebrovascular disease)-Contraindicated
2. Major vascular surgery-Contraindicated
3. Allergy to sulphonamides-Contraindcated
4. Hepatic impaired (Contraindicated in severe impairment)
5. Surgery

(Post CABG-Parecoxib is associated with increased risk of cardiovascular events and thrombolic events. Infection and poor wound healing complications)

1. Elderly

-Reduce dose for elderly woman <50kg

• Administration advice:

IM injection: Inject slowly and deeply into muscle.

IV injection: Give as a bolus directly into vein or into an IV line delivering sodium chloride 0.9% or glucose 5%

-Flush line before and after parecoxib injection to prevent precipitation when a second drug is given.

• Practice points:

–40mg is the maximum effective dose as higher doses do not have higher analgesic effect

-Onset of analgesia is approximately 15mins after injection. Duration of analgesia is 6-24 hours.

-Prodrug of valdecoxib (a selective COX-2 inhibitor associated with serious skin reactions)

*Has no effect on platelet function and thus does not promote bleeding during or after surgery.

————————————————Cox-3 Inhibitors (Analgesic)————————————————

• Paracetamol/Acetaminophen (US) (NON-OPIOID ANALGESIC)

–Analgesic efficacy is equivalent to aspirin but in therapeutic doses has only weak anti-inflammatory effects.

• Mechanism of action: (Not fully determined)

-Inhibits prostaglandin synthesis in the brain but hardly at all in the periphery. No effect on platelet function.

-Modulation of inhibitory descending serotonergic pathways.

-Anti-pyretic effect is probably due to reduced production of prostaglandins in the hypothalamus

• Clinical Indications:

 

(a)    Mild-moderate pain (including combination with dextropropoxyphene or codeine (OAA around 30 min after oral administration)

(b)   Fever

(c)    Migraine (with nausea and vomiting) *IN COMBINATION WITH metoclopramide

 

• Precautions:

 

1. Hepatic impaired (People with chronic liver disease may be at increased risk of liver damage following therapeutic overdose ie. 3x3000mg daily
2. Pregnancy-Safe to use. CAT A-AUS. Breastfeeding: Safe to use.
3. Sodium restriction-Soluble paracetamol products may contain large amounts of sodium
4. Phenylketonuria: Soluble paracetamol products may contain aspartame.

• Side effects/Unwanted effects

-Few and uncommon side effects.

*Common: Increased Aminotransferases

Toxic doses: 2-3 x therapeutic dose (Max adult recommended dose-3000mg per day)

(a)    Leads to renal and liver damage

àIt is normally inactivated in the liver by conjugation as glucorinide and sulphate

àHowever, at higher doses of paracetamol, enzymes for these pathways are exhausted and mixed function oxidases convert paracetamol to the toxic metabolite N-acetyl-b-benzoquinone imine.

àUsually it is further conjugated with glucorinide to prevent accumulation. At high doses, enzymes depleted.

àToxic intermediates accumulates and binds to macromolecules (causes cell death)

àAgents which stimulate glutathione production (e.g. acetylcysteine or methionine) can prevent liver damage if given early.

Rare side effects:

-Urticarial/Erythematous rash, drug fever and mucosal lesions

-Hypersensitivity reactions

-Neutropenia, Thrombocytopenia, Pancytopenia

-Acute hepatitis (only one case reported in AUS)

-Hypotension (IV)

• Administration advice:

-Give IV infusion over 15 mins.

-Oral tablets (Before a meal)

• Counselling:

-Many brands of paracetamol are available. Contained in many cough and cold products.

-Prevent overdosing by checking carefully which strength product is being used. Correct dose accordingly.

-Avoid using more than one product containing paracetamol at once. Too much paracetamol cause liver damage

Adult: Do not take more than 8 tablets or capsules (500mg strength) or 6 controlled release tablets each day.

Child: Give paracetamol strictly according to the dose and frequency instructions on the label and if pain and/or fever lasts for >48 hours, talk to the doctor.

 

• Practice points:

-Paracetamol may be used in all age groups and is preferred over NSAIDs for mild-to moderate pain (fewer side effects)

-Can be used when NSAIDs are contraindicated (e.g. increased risk of bleeding, Gastric ulcers present)

-Can use in osteoarthritis of all grades, paracetamol alone is preferred but under used.

-Used with NSAID treatment for all painful conditions, although evidence is sparse for superiority of this combination compared with NSAID alone.

 

Children and infants:

-They can tolerate low grade fever relatively well. Often responds to fluids and comfort. May not require paracetamol.

-Lack of awareness of the strengths of different pediatric products (e.g. infant drops, liquid paracetamol and use of >1 product containing paracetamol). May lead to dosage errors and toxicity.

-Educate parents and caregivers appropriately

Onset of action:

-Approximately 30 min after oral administration.

-Erratic and delayed OAA after rectal administration.

-Approximately 5-10 min after IV administration.

 

 

 

 

——————————Drugs taken along with Diclofenac for GIT protective effects:

Anti-ulcer medications:

• Misoprostol

–(Prostaglandin E1 analogue)

• Mechanism of action: (Protective effects)

*Increases secretion of mucus.

-Prostaglandin E1 analogue that protects GI mucosa by increasing the secretion of mucus when bound to prostaglandin receptors.

*Stimulates bicarbonate secretion in the duodenum

*Inhibits basal and stimulated acid secretion by a direct action on gastric parietal cells

 

• Clinical Indications:

 

(a)    Peptic ulcer disease (PUD)

(b)   Prevention of NSAID-related ulcers

(c)    Obstetric indications (e.g. termination of second trimester pregnancy)

(d)   Intrauterine fetal death

(*Can be combined with diclofenac-Prevent NSAID-induced ulcers)

 

• Precautions:

 

1. Cerebrovascular or coronary artery disease (CAD)-Misoprostol-induced peripheral vasodilation may destabilise cardiac disease
2. Predisposition to diarrhoea, dehydration

-Misoprostol induced diarrhea may worsen

3.    Surgery (Continue treatment during peri-operative period)

4.   Women (Ensure effective contraception during treatment)

5.   Pregnancy-CONTRAINDICATED. May induce labour by ripening cervix and increasing uterine

tone and contractility. CAT X-AUS

6.  Breastfeeding-Appears safe. Possibility of diarrhoea in child.

• Adverse effects/Side effects:

Common

*GIT effects: Diarrhoea, Abdominal pain, Nausea, Flatulence, Dyspepsia, Vomitting

Infrequent

1. Rash
2. Headache
3. Dizziness
4. Constipation
5. Uterine cramps
6. Bleeding: Heavy menstrual bleeding, Post-menopausal bleeding, Intermenstrual bleeding

 

• Counselling:

*Take with meals to reduce risk of diarrhoea. Tell the doctor if patient has symptoms such as black stools or vomit that looks like coffee grounds.

• Practice Points:

-Misoprostol 800mg daily is the optimum dose for preventing ulcers due to NSAIDs. Consider the combination product only for patients already stabilised on the same doses of single ingredient products.